The World Health Organization report of Infectious Disease deaths for 1995 indicated that there were more than 13 million deaths world-wide during that year. The majority of those deaths were caused by organisms that first make contact with and then either colonize or cross mucosal surfaces to infect the host. The overall morbidity caused by these organisms and other pathogens that interact with mucosal surfaces is impossible to calculate.
Traditional vaccine strategies that involve parenteral immunization with inactivated viruses or bacteria or subunits of relevant virulence determinants of those pathogens do not prevent those interactions. In fact, traditional vaccine strategies do not prevent infection but instead resolve infection before disease ensues. In some cases, HIV for example, once the virus crosses the mucosal surface and enters the host cell, be that a dendritic cell, an epithelial cell, or a T-cell, the host-parasite relationship is moved decidedly in favor of the parasite (HIV). In that case, as in many others, a vaccine strategy that does not prevent the initial infection of the host is unlikely to succeed.
Recently, a great deal of attention has focused on mucosal immunization as a means of inducing secretory IgA (sIgA) antibodies directed against specific pathogens of mucosal surfaces. The rationale for this is the recognition that sIgA constitutes greater than 80% of all antibodies produced in mucosal-associated lymphoid tissues in humans and that sIgA may block attachment of bacteria and viruses, neutralize bacterial toxins, and even inactivate invading viruses inside of epithelial cells. In addition, the existence of a Common Mucosal Immune System permits immunization on or at one mucosal surface to induce secretion of antigen-specific sIgA at distant mucosal sites. It is only now being appreciated that mucosal immunization may be an effective means of inducing not only sIgA but also systemic antibody and cell-mediated immunity.
The mucosal immune response can be divided into two phases (McGhee and Kiyono, 1993, Infect Agents Dis 12:55-73). First, the inductive phase involves antigen presentation and the initiation events which dictate the subsequent immune response. During the initiation events, antigen-specific lymphocytes are primed and migrate from the inductive sites (e.g., Peyer's patches in the enteric mucosa) through the regional lymph nodes, into the circulation and back to mucosal effector sites (e.g., lamina propria). Once these effector cells have seeded their effector sites, the second phase, or effector phase, of the mucosal immune response can occur. A significant difference between mucosal immunization and parenteral immunization is that both mucosal and systemic immunity can be induced by mucosal immunization while parenteral immunization generally results only in systemic responses.
Most studies conducted to date have dealt with the secretory antibody component of the mucosal response and the complex regulatory issues involved with induction of sIgA following mucosal immunization and not with the systemic antibody response or cellular immunity induced by mucosal immunization. In that regard, it is important to understand the type of helper T lymphocyte response induced by mucosal immunization since the type of helper T lymphocyte stimulated by an antigen is one of the most important factors for defining which type of immune response will follow. Mosmann and colleagues (Cherwinski et al., 1987, Journal of Experimental Medicine 166:1229-1244; Mosmann and Coffman, 1989, Annual Reviews of Immunology 7:145-173) discovered that there are at least two different types of helper T lymphocytes (Th) which can be identified based on cytokine secretion. Th1 lymphocytes secrete substantial amounts of IL-2 and INF-gamma and execute cell-mediated immune responses (e.g., delayed type hypersensitivity and macrophage activation), whereas Th2 lymphocytes secrete IL-4, IL-5, IL-6 and IL-10 and assist in antibody production for humoral immunity. Theoretically then, antigenic stimulation of one T helper cell subset and not the other would result in production of a particular set of cytokines which would define the resulting immune response.
The presence of IL-2 and INF-gamma coupled with an antigenic stimulus presented by macrophages in the context of Class II MHC molecules can initiate Th1 type responses. The ability of Th1 cells to secrete IL-2 and INF-gamma further amplifies the response by activating Th1 cells in an autocrine fashion and macrophages in a paracrine fashion. These activated leukocytes can release additional cytokines (e.g., IL-6) which may induce the proliferation and differentiation of antigen specific B lymphocytes to secrete antibody (the effector phase). In this scenario, the predominant isotype secreted by murine B lymphocytes is often IgG2a. In a second scenario (Urban et al., 1992, Immunol Rev 127:205-220), antigens such as allergens or parasites can effectively stimulate a Th2 lymphocyte response (the inductive phase). Presentation of such antigens to Th2 cells can result in the production of the lymphokines IL-4 and IL-5 which can induce antigen specific B lymphocytes to secrete IgE and IgG1 or induce eosinophillia, respectively (the effector phase). Furthermore, stimulated Th2 cells can secrete IL-10 which has the ability to specifically inhibit secretion of IL-2 and INF-gamma by Th1 lymphocytes and also to inhibit macrophage function.
While these representations are simplistic, it is obvious that the type of T helper cell stimulated affects the resultant cellular immune response as well as the predominant immunoglobulin isotype secreted. Specifically, IL-4 stimulates switching to the IgE and IgG1 isotypes whereas INF-gamma stimulates IgG2a secretion. Numerous studies, predominantly conducted in vitro, have suggested that IL-5, IL-6 and TGF-beta (Th3) can cause isotype switching to IgA.